Disease discovery and disease definition are critical first steps in elucidating pathogenetic mechanisms of cancer. Most insights into the molecular pathogenesis of lymphomas have followed on the heels of a precise elucidation of the disease entity based on clinical, pathological, or immunophenotypic grounds. Our work focuses on the definition of malignant lymphomas as tumors of the immune system, delineation of new disease entities, studies related to the pathophysiology of malignant lymphomas, and clinical correlations including prognosis and response to treatment. In July 2001, the WHO Classification of Tumours of the Hematopoietic and Lymphoid Tissues was published by the International Agency for Research on Cancer (IARC Press). This book culminated five years of work by more than 100 internationally recognized hematopathologists, hematologists and oncologists. This work reflects many of the contributions from our laboratory and others to define disease entities. It is a significant milestone, as it is the first classification of hematolymphoid neoplasia to receive worldwide acceptance. It is also a roadmap for future investigations, as it highlights areas requiring further investigation and study, such as diffuse large B-cell lymphomas and peripheral T-cell lymphomas. Granzyme M (GM) is a novel serine protease whose expression is highly restricted to natural killer (NK) cells, CD3(+)CD56(+) T cells, and gamma-delta T cells. Using a GM-specific monoclonal antibody, we analyzed the expression of GM in 214 mature T-cell and NK-cell lymphomas. GM was preferentially expressed in nasal NK/T-cell lymphomas (100%), gamma-delta T-cell lymphomas (100%), and intestinal T-cell lymphomas (85%). In contrast, GM expression was present at low prevalence in mycosis fungoides/Sezary syndrome (3%), anaplastic large-cell lymphoma (6%), panniculitis-like T-cell lymphoma (11%), and angioimmunoblastic T-cell lymphoma (0%) cases. Peripheral T-cell lymphomas of unspecified subtype showed an intermediate frequency (37%) of GM expression, consistent with their heterogeneous origin. We conclude that GM expression is a distinctive feature of the nasal NK/T-cell, gamma-delta T-cell, and intestinal T-cell lymphomas, and suggest that these tumors develop from lymphocytes involved in innate immunity. In a clinical study, we further elucidated the clinical features of gamma-delta T-cell lymphoma. TCR delta 1 cellular expression was assessed in skin biopsy specimens of 104 individuals with cutaneous T-cell lymphoma by immunohistochemistry. Both univariate (Kaplan-Meier) and multivariate (Cox regression) analyses were conducted to determine which variables (T-cell subtype, hemophagocytosis, histologic profile, age, sex, and adenopathy) were significantly associated with survival. Univariate analysis indicated that there was a statistically significant difference in survival between the patients with alpha beta cutaneous T-cell lymphoma and patients with gamma delta cutaneous T-cell lymphoma (P <.0001). There was also a statistically significant decrease in survival among patients who had subcutaneous involvement compared with patients who had epidermotropic and/or dermal involvement (P <.0001). Cox model analysis indicated that TCR delta 1 expression was the factor that was most closely associated with decreased survival (P <.0001). Among those patients with cutaneous gamma delta T-cell lymphoma (n = 33), there was a trend for decreased survival for patients who had histologic evidence of subcutaneous fat involvement in comparison with patients who had epidermotropic or dermal patterns of infiltration (P =.067). No other prognostic factors were identified as having a notable association with outcome in this subgroup. TCR delta 1 expression in primary cutaneous lymphomas is an independent prognostic factor associated with decreased survival. In collaborative studies with Dr. Louis Staudt and the LLMPP, we showed the value of gene profiling as assessed by microarray technology and immunohistochemistry in the subclassification of diffuse large B-cell lymphomas. Immunohistochemistry can be used as a surrogate for gene expression profiling, allowing the export of these advances to the routine pathology laboratory and the general medical community.